We examined the effect of calorie intake via enteral nutrition on diaphragmatic thickness and prognosis of mechanically ventilated patients with chronic obstructive pulmonary disease. Patients diagnosed as malnutrition were divided into observation and control groups. Both groups received conventional therapy and enteral nutrition. In the observation group, early adequate nutritional therapy was given, and the target calorie was gradually achieved within 1–3 days. In the control group, trophic feeding was provided, and the target calorie was gradually obtained after 7 days. Baseline clinical data were collected upon admission. Infection and inflammation indices, nutritional indices, and diaphragm indices were compared. Prognostic indices were compared, and the correlations of nutritional indices with diaphragmatic thickness and prognostic indices were analyzed using Pearson's analysis. The two groups had similar gender, age, heart rate, mean arterial pressure, arterial partial pressure of oxygen, acute physiology and chronic health evaluation II score, systemic inflammatory response syndrome score, multiple organ dysfunction (MODS) score, inflammation indices, nutritional indices, and diaphragmatic thickness indices upon admission (P › 0.05). Compared with values before enteral nutrition, the levels of procalcitonin, tumor necrosis factor-α, interleukin-6, and interleukin-8 significantly declined after treatment in both the groups, but greater decrease in the observation group (P ‹ 0.05). Diaphragmatic thickness at the end of expiration had no significant difference between the two groups at each time point, but diaphragmatic thickness at the end of inspiration and diaphragmatic thickening fraction significantly increased on the 7th day of enteral nutrition and after weaning, which were more significant in the observation group (P ‹ 0.05). No significant difference was found in the length of stay in intensive care unit between the two groups (P › 0.05), while the duration of mechanical ventilation, weaning success rate within 14 days, and morbidity and mortality rates of ventilator-associated pneumonia had significant differences (P ‹ 0.05). Nutritional indices were positively correlated with diaphragmatic thickness at the end of inspiration, diaphragmatic thickening fraction, duration of mechanical ventilation, and morbidity and mortality rates of ventilator-associated pneumonia, but negatively correlated with the weaning success rate within 14 days. Different enteral nutrition regimens can significantly improve the nutritional status and diaphragmatic function, inhibit the inflammatory response, shorten the duration of mechanical ventilation, and enhance the clinical treatment and prognosis effect on mechanically ventilated patients with chronic obstructive pulmonary disease